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The Panzerhund was one of the first prototype robots to come out of General Deathshead's workshop. According to a newspaper article found in-game, it was first deployed on the Eastern Front, creating chaos along the Russian ranks as it tore through the battlefield.

Initially despite the introduction of the Panzerhund, the most common German canine unit to be seen on the battlefield in the Western theaters during the late 40s was the Kampfhund; the Panzerhunde encountered in 1946 by B.J. Blazkowicz appeared during the crash landing upon the beaches of Deathhead's Compound, before he and the other remaining Allied troops scaled the castle walls. Despite their appearance and apparent invulnerability to most attacks, they are taken out by B.J. using an anti-aircraft gun. Upon exiting the bunkers surrounding Deathshead's castle, B.J. is attacked and nearly killed by a Panzerhund, but is saved when Private Probst Wyatt III tricks the beast into catching a live grenade in its mouth, destroying it.

However this was actually not the first time Blazkowicz had personally encountered a Panzerhund. During the events of the Old Blood, B.J. had twice encountered a prototype of the Panzerhund. It is first encountered after B.J. sees Rudi Jäger take Wesley to be interrogated. It walks out of two sliding doors and B.J. must hide from it to avoid being killed. The same one that is encountered that time is seen again trying to jump up and kill B.J. very similar to how another one did in the New Order. It is seen again during a shootout at Paderborn Bridge, and B.J. must kill it to advance.

Alongside Deathshead, a key figure in the creation of the Panzerhund was a certain Dr. Ernst Brandt who designed the Artificial Intelligence system used in the robot.

The Panzerhund 1960 is the evolution of the first prototypes and production model created by General Deathshead during the war. As envisioned by the General in one of his fevered visionary dreams, it is a super-efficient murder machine encased in titanium steel armor and fitted with bone-crushing metal jaws that can cut through the thickest of body armor.

The new, far more deadly Panzerhund can be seen several times during the campaign, each time posing a lethal threat to the player. A 1960s Panzerhund requires far more firepower to bring it down than its 1940s counterpart.

B.J. first encounters the 1960 Panzerhund while infiltrating the Eisenwald Prison in Berlin, but eventually incapacitates it in electrified water. Following Bobby Bram's suicide bombing of the London Nautica, B.J. evades and kills another Panzerhund as he makes his way into the building. Later, B.J. fights and destroys two more Panzerhunde while escaping the raid on the Kreisau Circle's hideout.

The Panzerhund makes a comeback in Wolfenstein 2: The New Colossus, this time in the 1961 Nazi-occupied United States. This model features an upgraded body and has a flamethrower in its mouth.

A Panzerhund appears as the titular deuteragonist of the in-game film Liesel. The main character Peggy summons Liesel with a whistle and orders her to save a sheriff from his overturned truck. Liesel does so, but also destroys the truck, to Peggy's disappointment.

While searching for Horton in the ruins of New Orleans, B.J. encounters Panzerhunde patrolling the streets as part of the citywide purge.

At some point, Horton's resistance cell captured and reprogrammed a Panzerhund to fight its former masters. B.J. himself rides the Panzerhund, killing as many Nazis as possible, in order to buy Horton and other survivors of the New Orleans ghetto time to escape.

Also Joseph Stallion had managed to steal a Panzerhund during his escape from a prison in Chicago.